This research will be done primarily in Brazil at Hospital de Clinicas de Porto Alegre in collaboration with Dr. Temis M. Felix, as an extension of NIH grant #R37-DE-08559. Orofacial clefts are among the most common birth defects. 70% are nonsyndromic, that is, are not associated with other congenital anomalies or developmental impairment. They occur as a complex trait as a result of an interaction between genetic and environmental factors. A few genes have already been identified as contributing to clefting including the developmental genes IRF6, MSX1 and TGFB3. However, other genes including those involved in the folic acid pathway are excellent candidates for contributing to its etiology as well. These genes may interact with environmental factors including nutritional profiles in pregnancy. The aim of this research is to study the folate pathway genes and their interaction with environmental factors in a population that has been participating in a clinical trial on the use of folic acid for prevention of recurrences in clefting. We are collecting clinical data, DNA and biochemical samples in non- syndromic clefts case/parent triads. Biochemical studies will include the measurement of folate, vitamin B12 and homocysteine, an important marker of the folic acid metabolism. We will genotype polymorphisms in folic acid pathway genes and analyze the gene-gene interaction and gene-environmental interactions. This research will contribute to the understanding of genetic and environmental factors related to clefts and contribute to the prevention of recurrence of clefts in high risk group population that is a candidate for nutritional interventions. As a FIRCA proposal it will establish a program of productive research in a facility with a strong record of genetic and biochemical investigation. [unreadable] [unreadable] [unreadable]